Our population is growing older, and the greatest increases are occurring in the 85 and older age group. This demographic trend places in jeopardy the existing structures for healthcare delivery and social security. Our goal is to provide the fundamental knowledge that will allow the creation of preventive and compensatory interventions to improve the functional status of our seniors and thus to prevent a dramatic expansion of the nursing home population. Both genetic and environmental factors play a role in aging and the quality of life in the elderly. We will identify characteristics of an individual's energy metabolism that predispose to long life and retention of physical and cognitive capacity, promoting the sense of well being associated with healthy aging. This will be done by examining metabolic factors at the genetic, molecular, cellular, and physiologic levels, and by scrutinizing environmental influences in nonagenarians and younger subjects. Population genetic methods will be applied to candidate genes implicated in metabolism and stress resistance. This will be coupled to the analysis of global profiles of glucose-regulated gene expression in conjunction with an examination of T cell function. Body composition, resting metabolic rate, and free-living energy expenditure determinations, as well as assessment of oxidative stress, will provide the physiologic parameters. Physical function will be assessed by physical examination, activity of daily living (ADL) surveys, and ADL-based tests of physical fitness. Cognitive capacity will be ascertained by examination of individual differences in general intellectual abilities and of episodic memory. Demographic, familial, medical, and lifestyle factors will contribute to our analysis. Pilot interventions will also be part of our investigation. These studies will be carried out in five Projects, which will be supported by an Administrative Core, housing the Medical Assessment Unit, a Sampling and Data Management Core, which will provide statistical support and maintain a central, secure, web-based database, and a Recruitment and Clinical Testing Core, which will operate a one-stop, central testing facility. The research program is interdisciplinary, spanning the genetic and molecular through the physiologic to physical function and psychology. Our purpose is to provide the bases for multi-domain modeling of function and disablement in the elderly population. The proposed studies have important implications for aging, musculoskeletal and infectious diseases, as well as diabetes and mental health.